The HDAC inhibitor AR42 interacts with pazopanib to kill trametinib/dabrafenib-resistant melanoma cells in vitro and in vivo.

Studies focused on the killing of activated B-RAF melanoma cells by the histone deacetylase (HDAC) inhibitor AR42. Compared to other tumor cell lines, PDX melanoma isolates were significantly more sensitive to AR42-induced killing. AR42 and the multi-kinase inhibitor pazopanib interacted to activate: an eIF2?-Beclin1 pathway causing autophagosome formation; an eIF2?-DR4/DR5/CD95 ...
pathway; and an eIF2?-dependent reduction in the expression of c-FLIP-s, MCL-1 and BCL-XL. AR42 did not alter basal chaperone activity but increased the ability of pazopanib to inhibit HSP90, HSP70 and GRP78. AR42 and pazopanib caused HSP90/HSP70 dissociation from RAF-1 and B-RAF that resulted in reduced 'RAF' expression. The drug combination activated a DNA-damage-ATM-AMPK pathway that was associated with: NF?B activation; reduced mTOR S2448 and ULK-1 S757 phosphorylation; and increased ULK-1 S317 and ATG13 S318 phosphorylation. Knock down of PERK, eIF2?, Beclin1, ATG5 or AMPK?, or expression of I?B S32A S36A, ca-mTOR or TRX, reduced cell killing. AR42, via lysosomal degradation, reduced the protein expression of HDACs 2/5/6/10/11. In vivo, a 3-day exposure of dabrafenib/trametinib resistant melanoma cells to the AR42 pazopanib combination reduced tumor growth and enhanced survival from ~25 to ~40 days. Tumor cells that had adapted through therapy exhibited elevated HGF expression and the c-MET inhibitor crizotinib enhanced AR42 pazopanib lethality in this evolved drug-resistant population.
Mesh Terms:
Angiogenesis Inhibitors, Animals, Antineoplastic Combined Chemotherapy Protocols, Autophagosomes, Blotting, Western, Cell Line, Tumor, Cell Survival, Drug Resistance, Neoplasm, Drug Synergism, Eukaryotic Initiation Factor-2, Histone Deacetylase 6, Histone Deacetylase Inhibitors, Histone Deacetylases, Humans, Imidazoles, Kaplan-Meier Estimate, Male, Melanoma, Mice, Nude, Microscopy, Fluorescence, Oximes, Phenylbutyrates, Pyridones, Pyrimidines, Pyrimidinones, RNA Interference, Signal Transduction, Sulfonamides, Xenograft Model Antitumor Assays
Oncotarget
Date: Mar. 07, 2017
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